The underlying premise of this proposal is that increased in vivo production of B cell activating factor belonging to the TNF family (BAFF), a vital B cell survival and costimulatory factor, is an important and central contributor to disease development and/or maintenance in many, but not necessarily all, SLE patients. The entry of BAFF antagonists into human clinical trials notwithstanding, a greater insight into several critical issues is needed before treatment with BAFF antagonists can realize their full clinical potential. First, in vivo conditions under which BAFF overexpression leads to disease versus those under which BAFF overexpression does not lead to disease have largely been unexplored. Development of an in vivo model in which BAFF-driven disease rapidly develops would facilitate experimental dissection of the requisite pathways. Conversely, development of an in vivo model in which constitutive overexpression of BAFF is incapable of driving autoimmunity would facilitate dissection of pathways that render resistance to BAFF. Second, the relative importance of the individual BAFF receptors to BAFF-driven autoimmune disease is not known and needs to be identified. Third, it is not known whether the disease-promoting effects of BAFF are consequent to production of pathogenic autoantibodies or are consequent to effects on B cells that are largely independent of autoantibody production. To begin to address these issues, the following questions are posed: 1a) Does persistent BAFF overproduction synergize with an underlying incomplete genetic predisposition to SLE and result in rapid development of disease? 1b) Does a SLE suppressor genetic region protect against the disease-promoting effects of persistent BAFF overexpression? 2a) Will elimination of BAFF ameliorate development of autoimmune disease in a SLE-prone host? 2b) Will elimination of BAFFR and/or BCMA ameliorate development of disease in a host that naturally is SLE-prone or in a host with BAFF-driven autoimmune disease? 3) Does BAFF promote autoimmune disease in an autoantibody-independent manner? The results from these in vivo studies in mice should yield important information regarding BAFF-driven disease that will help set a solid foundation for subsequent focused in vivo clinical trials in human SLE patients. [unreadable] [unreadable] [unreadable] [unreadable]